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The Role of Tumor Necrosis Factor  in Modulating the Quantity of
Peripheral Blood-Derived, Cytokine-Driven Human Dendritic Cells and Its
Role in Enhancing the Quality of Dendritic Cell Function in
Presenting Soluble Antigens to CD4+ T Cells In Vitro
Bing-guan Chen,
Yijun Shi,
Jeffrey D. Smith,
David Choi,
James D. Geiger, and
James J. Mulé
From the Department of Surgery, University of Michigan Medical
Center, Ann Arbor, MI.
Because dendritic cells (DC) are critically involved in both
initiating primary and boosting secondary host immune responses, attention has focused on the use of DC in vaccine strategies to enhance
reactivity to tumor-associated antigens. We have reported previously
the induction of major histocompatibility complex class II-specific T-cell responses after stimulation with tumor
antigen-pulsed DC in vitro. The identification of in vitro conditions
that would generate large numbers of DC with more potent
antigen-presenting cell (APC) capacity would be an important step in
the further development of clinical cancer vaccine approaches in
humans. We have focused attention on identifying certain exogenous
cytokines added to DC cultures that would lead to augmented human DC
number and function. DC progenitors from peripheral blood mononuclear cells (PBMC) were enriched by adherence to plastic, and the adherent cells were then cultured in serum-free XVIVO-15 medium (SFM) for 7 days
with added granulocyte-macrophage colony-stimulating factor (GM-CSF)
and interleukin-4 (IL-4). At day 7, cultures contained cells that
displayed the typical phenotypic and morphologic characteristics of DC.
Importantly, we have found that the further addition of tumor necrosis
factor  (TNF) at day 7 resulted in a twofold higher yield of DC
compared with non-TNF-containing DC cultures at day 14. Moreover,
14-day cultured DC generated in the presence of TNF (when added at
day 7) demonstrated marked enhancement in their capacity to stimulate a
primary allogeneic mixed leukocyte reaction (8-fold increase in
stimulation index [SI]) as well as to present soluble tetanus toxoid
and candida albicans (10- to 100-fold increases in SI) to purified
CD4+ T cells. These defined conditions allowed for
significantly fewer DC and lower concentrations of soluble antigen to
be used for the pulsing of DC to efficiently trigger specific T-cell
proliferative responses in vitro. When compared with
non-TNF-supplemented cultures, these DC also displayed an increased
surface expression of CD83 as well as the costimulatory molecules, CD80
and CD86. Removal of TNF from the DC cultures after 2 or 4 days
reduced its enhancing effect on DC yield, phenotype, and function.
Thus, the continuous presence of TNF over a 7-day period was
necessary to achieve the maximum enhancing effect observed.
Collectively, our findings point out the importance of exogenous TNF
added to cultures of cytokine-driven human DC under serum-free
conditions, which resulted in an enhanced number and function of these
APC. On the basis of these results, we plan to initiate clinical
vaccine trials in patients that use tumor-pulsed DC generated under
these defined conditions.
Blood, Vol. 91 No. 12 (June 15), 1998:
pp. 4652-4661
© 1998 by The American Society of Hematology.
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